Calcitriol, also known as 9,10-Secocholesta-5,7,10(19)-tricne-1,3,25-triol, 1 .alpha., 25-dihydroxycholecalciferol, or 1.alpha., 25-dihydroxyvitamin D.sub.3, is the biologically active form of vitamin D.sub.3 which promotes intestinal calcium transport and bone calcium resorption. It is formed in the kidney during the second of two successive hydroxylations of vitamin D, and is administered therapeutically for the treatment of vitamin D-dependent rickets, osteoporosis, hypocalcemia (particularly when associated with hypoparathyroidism), and calcium metabolism disorders associated with renal failure.
Calcitriol is supplied commercially in two forms. Rocaltrol.RTM. (calcitriol) capsules (Roche Labs) provide a solid form for oral administration, while Calcijex.RTM. (calcitriol) (Abbott Labs) provides a solution for intravenous administration, which is particularly useful for chronic renal dialysis patients. The intravenous solution is supplied as 1 ml ampules containing either 1 mcg or 2 mcg of calcitriol. The ampules are stored at 15-30.degree. C. (59-86.degree. F.) and are formed of amber glass to protect the solution from light.
Calcitriol is a colorless compound which can be degraded by light and oxygen. Therefore, it is supplied in combination with a metal ascorbate salt antioxidant, such as sodium ascorbate, and a chelating agent. The headspace of the calcitriol ampule is filled with nitrogen gas to provide an inert atmosphere. However, even in the airtight ampule, the solution retains some oxygen and the reaction of the metal ascorbate antioxidant with the residual oxygen ultimately causes the clear solution to turn yellow. Since drug products are periodically inspected for discoloration, a significant amount of therapeutically useful product is discarded due to antioxidant discoloration.
A calcitriol composition which is stored in an ampule has previously been described by Conway et al. (U.S. Pat. No. 4,308,264, issued Dec. 29, 1981). Although the sealed glass ampule provides the advantage of product storage with nitrogen gas in the headspace to provide a more inert environment, this form of drug packaging has even more significant disadvantages for clinical use. For example, sealed glass ampules must be broken open in order to access the medication, exposing the health care provider to risk of injury from broken glass. Glass fragments can enter the solution as the ampule is broken, often requiring the use of a sterile filter, with additional effort and expense, to remove the solution from the open ampule. Breaking the ampule requires that it be handled, usually not within a sterile environmnent, increasing the risk of both microbial and blood contamination. The ampule has broken glass edges which are difficult to sterilize before the needle is inserted. Once the ampule is broken the entire contents must be used or, if only a part of the contents are used, the remainder must be discarded. It is also not unusual for an ampule to shatter completely upon opening, spilling the contents and potentially causing injury to the individual trying to open it. Ampule packaging is therefore used only when the physical and chemical stability of the contents requires it.
There is currently a need for alternative packaging systems that can maintain the stability of aqueous calcitriol solutions.